THE PARASYMPATHETIC NERVOUS SYSTEM

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THE PARASYMPATHETIC NERVOUS SYSTEM
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PARASYMPATHETIC INNERVATION FROM BRAIN
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PARASYMPATHETIC INNERVATION FROM SACRAL CORD
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CHOLINERGIC FIBER
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ACETYLCHOLINE
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CHOLINE
ACETIC ACID
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NATURE OF CHOLINERGIC RECEPTORS

• MUSCARINIC RECEPTORS ARE METABOTROPIC THERE ARE
  SEVERAL SUBTYPES
• M1 M2 M3 M4 M5

• NICOTINIC RECEPTORS ARE IONOTROPIC THERE ARE TWO
  SUBTYPES
• NN NM

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MUSCARINIC RECPTORS ARE ASSOCIATED WITH
G-PROTEINS biochemical responses
electrophysiological responses NICOTINIC
RECPTORS FORM ION CHANNELS
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NICOTINIC RECEPTORS SUBTYPES
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MUSCARINIC RECEPTOR SUBTYPES
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• AUTONOMIC GANGLIA
• Nicotonic sites
• Muscarinic sites

Reproduced from Basic and Clinical Pharmacology,
Page 87

• ADRENAL MEDULLA
• Nicotonic sites Release of epinephrine (90) and
  norepinephrine (10) into the circulation.

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• END PLATE OF SKELETAL MUSCLE FIBER

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PARASYMPATHETIC INNERVATION TO THE EYE
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NITRIC OXIDE MEDIATED VASODILATION

• cyclic GMP?smooth muscle relaxation?vasodilation

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CARDIOVASCULAR RESPONSES TO LOW AND HIGH DOSES OF
ACETYLCHOLINE
LOW DOSE
HIGH DOSE
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ACETYLCHOLINE
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METHACHOLINE
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BETHANECHOL
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CARBACHOL
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ACETYLCHOLINESTERASE ENZYME- ACTIVE CENTER
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ACH IS A SUBSTRATE FOR AChE
. 1
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ACETYLATION OF AChE AND LIBERATION OF CHOLINE
. 6,7
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ACETYLATED-AChE UNDERGOES WATER HYDROLYSIS
. 8
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ACETYLATED-AChE UNDERGOES WATER HYDROLYSIS - 5
. 12

• Release of acetic acid, liberation of AChE

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INHIBITION OF ACETYLCHOLINESTERASE

• Inhibition of acetylcholinesterase leads to
  accumulation of acetycholine at all cholinergic
  receptors in the body.

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EDROPHONIUM
. 13

• A short-acting reversible inhibitor of AChE

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CARBAMYL INHIBITORS OF AChE
CARBAMYL INHIBITORS OF ACETYLCHOLINESTERASE
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CARBAMIC ACID

• Derivatives of carbamic acid inhibit
  acetylcholinesterase

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NEOSTIGMINE

• Neostigmine is an example of a carbamyl inhibitor
  of AChE.

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NEOSTIGMINE
. 15
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AChE BINDS NEOSTIGMINE
. 16

• Tetrahedral formation and electron rearrangement

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CARBAMYLATED AChE
. 17

• 3-Hydroxyphenyltrimethylammonium is released

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HYDROLYSIS OF CARBAMYLATED AChE
. 19

• Hydrolysis of carbamylated AChE proceeds slowly

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HYDROLYSIS OF CARBAMYLATED AChE - 2
. 19a

• Tetrahedral formation, electron rearrangement,
  liberation of AChE and dimethylcarbamic acid

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CARBAMYL INHIBITORS OF AChE
ORGANOPHOSPHATE INHIBITORS OF ACETYLCHOLINESTERAS
E
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GENERAL FROMULA FOR ORGANOPHOSPHATE INHIBITORS OF
AChE
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DIISOPROPYLFLUOROPHOSPHATE
. 20

• DFP irreversibly inhibits AChE

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AChE IS PHOSPHORYLATED BY DFP
. 22

• HF is released and AChE is irreversibly inhibited

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HYDROLYSIS OF PHOSPHORYLATED AChE
. 23

• Hydrolysis of phosphorylated AChE is a very slow
  reaction

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HYDROLYSIS OF PHOSPHORYLATED AChE LEADS TO ITS
LIBERATION
. 24a

• Diisopropylphosphoric acid is formed

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CONSEQUENCES OF ORGANOPHOSPHATEPOISONING

• Hydrolysis of phosphorylated AChE proceeds so
  slowly that functionally the enzyme is
  irreversibly inhibited.
• Accumulation of ACh at the end plate of skeletal
  muscle fibers leads to depolarization blockade.
• Skeletal muscle paralysis occurs. Death is due to
  respiratory muscle paralysis.
• Accumulation of ACh at neuroeffector sites
  (cardiac muscle, smooth muscles, glands) leads to
  autonomic disturbances.
• Effects observed are associated with excessive
  stimulation of muscarinic receptors.

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THERAPY OF ORGANOPHOSPHATEPOISONING

• Pralidoxime is used to reactivate the
  phosphorylated enzyme to allow recovery of
  skeletal muscle function
• Atropine is used to block the effects of ACh at
  neuroeffector sites
• Remove the individual from the source of
  contamination
• Provide mechanical ventilation if necessary

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PRALIDOXIME

• Pralidoxime does not reverse inhibition of
  carbamylated-AChE and should not be used in cases
  where AChE is inhibited by carbamyl inhibitors.
• Pralidoxime in high doses can inhibit
  acetylcholinesterase by binding to the anionic
  site of the enzyme.

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REACTIVATION OF PHOSPHORYLATED
ACETYLCHOLINESTERASE BY PRALIDOXIME

• In the U.S., pralidoxime is used to reactivate
  phosphorylated-AChE.
• The nucleophilic site of pralidoxime (NOH) has a
  high affinity for the phosphorus atom of the
  phosphorylated enzyme.
• Pralidoxime in high doses can inhibit
  acetylcholinesterase by binding to the cationic
  site of the enzyme.
• Pralidoxime does not reverse inhibition of
  carbamylated-AChE.

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PRALIDOXIME HAS A NUCLEOPHILIC SITE
. 25
NH2OH (hydroxylamine)

• Pralidoxime is choline esterase reactivator

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PRALIDOXIME REACTS WITH P-AChE (1)
. 26

• Pralidoxime attacks the phosphorus atom of P-AChE

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PRALIDOXIME REACTS WITH P-AChE (2)
. 27

• Complex formation

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P-AChE IS LIBERATED BY PRALIDOXIME
. 28

• An oxime phosphonate is formed

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AGING OF P-ACETYLCHOLINESTERASE (1)

• Hydrolysis of phosphorylated acetylcholinesterase
  is so slow that the majority of the enzyme
  molecules become aged.
• Aging refers to the loss of an alkyl group from
  the phosphorylated enzyme.
• Pralidoxime must be given before AChE becomes
  aged.
• Pralidoxime is ineffective against the aged
  enzyme.

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AGING OF P-ACETYLCHOLINESTERASE (2)
. 29
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DETERMINING PROPER DOSE OF ACH-ESTERASE INHIBITOR
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CONVERSION OF PARATHION TO PARAOXON
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CONVERSION OF MALATHION TO MALAOXON
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MALATHION METABOLISM

• Rapidly metabolized by birds and mammals
• Plasma carboxylesterases are involved
• Insects do not hydrolyze the drug
• Organophosphates inhibit the carboxylesterase
  enzyme and therefore inhibit the metabolism of
  malathion

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MALATHION CAN BE HYDROLYZED BY BIRDS AND MAMMALS
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NERVE AGENT VX
Chemical name O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL
)METHYL-PHOSHONOTHIOLATE Trade name
PHOSPHONOTHIOIC ACID
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MUSCARINIC RECEPTOR BLOCKING AGENTS
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WHEN THE MUSCARINIC ACTIONS OF ACETYLCHOLINE ARE
BLOCKED, THE NICOTINIC EFFECTS REMAIN
X
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X
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X
X
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Changes in Accomodation and Pupillary Diameter
after Administration of an Antimuscarinic Agent
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RESPONSE OF HEART TO DOSES OF ATROPINE
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Heart
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EFFECT OF ATROPINE IN RELATION TO DOSAGE
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DOSE EFFECT
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DOSE EFFECT
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DOSE EFFECT
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DOSE EFFECT
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DOSE EFFECT
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The previous five slides are reproduced
from Goodman and Gilmans THE PHARMACOLOGICAL
BASIS OF THERAPEUTICS
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THE SYMPATHETIC NERVOUS SYSTEM
Use the following slide along class notes with to
review the sympathetic neuron.
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THE ADRENERGIC NEURON